Biosafety Committees and Biological Materials Oversight: Past, Present and Future for Clinical Research

Transcription

1 Biosafety Committees and Biological Materials Oversight: Past, Present and Future for Clinical Research HealthCare Compliance Association / Chris Jenkins, PhD, MPH, RBP, CHMM Overview Biosafety Past Biosafety Present Biosafety Future 1

2 Biosafety Past HCCA / Chris Jenkins, PhD, MPH, RBP, CHMM What are Biological Materials? Biological Materials or Biohazards are infectious agents or hazardous biological materials that present a risk or potential risk to the health of humans, animals or the environment. CDC BMBL 5th ed. Examples: Whole or Wild-type Microorganisms Biological toxins Blood or other potentially infectious materials Recombinant or synthetic DNA resulting in organisms Image courtesy of the CDC 2

3 Recombinant and Synthetic Nucleic Acids Molecules that are constructed outside living cells by joining natural or synthetic DNA segments to DNA molecules that can replicate in a living cell, or molecules that result from the replication of those described above. National Institutes of Health, 2013 NIH funded research involving recombinant DNA (and in March, 2013, recombinant or synthetic nucleic acids, rsna) requires a risk assessment by a local Institutional Biosafety Committee. Image courtesy of the Scientific American Recombinant and Synthetic Nucleic Acids Molecules that are constructed outside living cells by joining natural or synthetic DNA segments to DNA molecules that can replicate in a living cell, or molecules that result from the replication of those described above. National Institutes of Health, 2013 NIH funded research involving recombinant DNA (and in March, 2013, recombinant or synthetic nucleic acids, rsna) requires a risk assessment by a local Institutional Biosafety Committee. Image courtesy of the Scientific American 3

4 History of Recombinant DNA Technology and Oversight Dr. Kornberg, 1968 U.S. Senate Subcommittee Vettel, 2006 Moratorium on rdna experimentation after Paul Berg generated first genetically modified replication competent E. coli in 1973 Jackson, Symons, and Berg, 1972 Gordon Conference Session request to National Academy of Sciences Singer and Sol, 1973 Assessment of recombinant DNA risks to be handled at Asilomar State Beach Berg, Baltimore et al, 1974 Above, Dr. Frederickson, Director of the NIH, Below, Dr. Paul Berg. Images courtesy of NIH and Nobel Institute Asilomar Conference The primary goal of the meeting was whether to lift the recombinant DNA moratorium and under what set of prescribed conditions. Berg, Baltimore et al., 1975 While little data beyond Berg s experiment existed at the time, despite opposition, the Conference ended with the understanding rdna research should proceed but under strict guidelines. Berg and Singer, , NIH Guidelines for Research Involving Recombinant DNA Molecules issued Frequent revisions through 2013 Images courtesy of NIH 4

5 The Role of the IBC & Risk Assessment Institutional Biosafety Committee (IBC) Capability to assess the safety of rdna research Be able to identify any potential risk to public health or the environment (NIH Guidelines, 2013) Risk Assessment Identify hazardous characteristics Evaluate exposure and consequences Determination BSL, work practices, safety equipment, and facility design to prevent exposure (CDC BMBL 5th ed., 2010) Microsoft Office open source images United States Regulatory Oversight of Biological Materials in Research NIH rdna Dual Use Research of Concern Gene Therapy CDC/USDA Select Agent Program Importation Federal OSHA Bloodborne Pathogens General Duty Clause Others Peripherally Associated Images courtesy of respective government entities 5

6 Figure 1. Biosafety & Biocontainment Regulations, Standards, and Guidelines Pertinent to High Containment and Maximum Containment Research (USDA Federal Task Force, 2009) Figure 2. Biosafety & Biocontainment Oversight (USDA Federal Task Force, 2009) 6

7 Figure 2. Biosafety & Biocontainment Oversight (USDA Federal Task Force, 2009) Biosafety Levels 1 & 2 BSL 1 BSL 2 7

8 Biosafety Present HCCA / Chris Jenkins, PhD, MPH, RBP, CHMM 2013 Survey of IBCs Survey: Specific Aim #1: To investigate United States life sciences regulation for research involving biological materials to assess the adequacy of biosafety and biosecurity oversight. Specific Aim #2: To evaluate IBCs charged to oversee research with biological materials to determine whether additional guidance and regulation is needed to protect staff, biological materials, and public health. 8

9 Survey Methodology Cross-Sectional Survey of NIH-OBA Registered IBCs FOIA #40395 (August, 2012), 857 FOIA #41293 (May, 2013), 866 FOIA #42013 (December, 2013), 868 Survey Design 22 Questions Institutional Type and Constituency of the IBC Biological Materials Review Protocol Review Determinations NIH-OBA Registered IBCs : 12 IBCs added per year : 43 IBCs added per year Year ( ) 9/11 and Anthrax Letters 9

10 IBC Protocols By Year 2000 IBC Protocols by Year from 22 Institutions y = x R² = Count Y1976 Y1977 Y1978 Y1979 Y1980 Y1981 Y1982 Y1983 Y1984 Y1985 Y1986 Y1987 Y1988 Y1989 Y1990 Y1991 Y1992 Y1993 Y1994 Y1995 Y1996 Y1997 Y1998 Y1999 Y2000 Y2001 Y2002 Y2003 Y2004 Y2005 Y2006 Y2007 Y2008 Y2009 Y2010 Year Institutional Case Study 10

11 Observed Trends in Biological Materials Oversight and IBCs Research involving biological materials has increased over time Protocol review data Expansion of IBC review beyond NIH Guidelines and Select Agent requirements Institutional support minimal beyond staffing Total IBC Protocols by Year from 22 Institutions Y1976 Y1978 Y1980 Y1982 Y1984 Y1986 Y1988 Y1990 Y1992 Y1994 Y1996 Y1998 Y2000 Y2002 Y2004 Y2006 Y2008 Y2010 Biosafety Future HCCA / Chris Jenkins, PhD, MPH, RBP, CHMM 11

12 Gene Therapy Involves delivery of therapeutic genes into the human body to correct disease conditions created by faulty genes Two primary strategies Ex vivo gene therapy In vivo gene therapy Ex vivo Gene Therapy Cells from diseased person are removed Cells are modified in the lab Modified cells are reintroduced to the patient Generally, more effective than in vivo 12

13 In vivo Gene Therapy Introduces genes directly into tissues or organs without removing body cells Challenge is delivering only to intended tissues Viruses, bacteria, and plasmids act as vectors for gene delivery some vectors injected directly into tissue Delivery of Therapeutic Genes Therapeutic genes often called payload May require longterm expression of corrective gene Others require rapid expression for short periods of times 13

14 Viral Vectors Viral vectors use viral genome to carry therapeutic gene(s) and to infect human body cells Adenovirus (common cold) Adeno-Associated Virus Retrovirus (HIV) Herpes Simplex Virus (cold sores) Vaccinia Virus Viruses must be engineered so that they can neither produce disease nor spread beyond targeted organs and tissues Vector Transfection Targeted gene therapy may result since some viruses infect certain body cells Adenoviruses infect both dividing and non-dividing cells effectively Adeno-Associated viruses do not cause illness in humans, can infect a wide variety of cells, & integrate 95% of time in same location Retroviruses are of interest because they insert DNA in to the genome of host where it remains permanently (integration), but often, randomly Herpes simplex viruses (HSV-1) strain primarily affects central nervous system (CNS) May help develop treatments for Alzheimer s, Parkinson s, etc. Although viral vectors may help, most human cells are not easily transfected 14

15 Unresolved Questions Can gene expression be controlled in the patient? What happens if normal gene is overexpressed? How long will the therapy last? What is the best vector to use? What is the minimum number of cells needed to infect to achieve success? Regulatory oversight flux? Gene Therapy Regulatory Issues NIH NIH Guidelines and IBC review apply only if Sponsor or entity receives NIH funding for rsna Take home message for clinical entities: Ask the Sponsor if the product is a recombinant Find out if you (the entity) or the Sponsor receives $1 of NIH funding which would then trigger IBC review. 15

16 Curing Genetic Disease More than 3,000 human genetic diseases are caused by single gene mutations These are strong candidates for treatment by gene therapy Cystic Fibrosis Huntington s disease Tay-Sachs Hemophilia Sickle cell disease Phenylketonuria First Human Gene Therapy Ashanti de Silva (4 years old) with severe combined immunodeficiency (SCID) treated in 1990 at NIH in Maryland Lacked functioning immune system because of a defect in gene called adenosine deaminase (ADA), which is involved in metabolism of datp (nucleotide precurosor used for DNA synthesis) Accumulations of datp are toxic to T cells Normal gene cloned into vector introduced into nonpathogenic retrovirus 16

17 First Human Gene Therapy Success Ex vivo approach used T cells isolated from blood Required multiple treatments Within a few months, T cell numbers increased After 2 years, ADA enzyme activity was high She is currently enjoying a healthy life Risks of Gene Therapy Discussions of safety intensified when 18-year old Jesse Gelsinger died during a clinical trial at the University of Pennsylvania in Complications related to adenovirus that was used. Ornithine transcarbamylase deficiency (affects ability to break down dietary amino acids) 1 st person to die of complications resulting from gene therapy. 17

18 Success of Gene Therapy Success in Rhys Evans, a child born with X-linked Severe Combined Immunodeficiency Syndrome (SCIDS aka bubble boy), in 2002 The team took stem cells that gave rise to immune cells from the boy s bone marrow They used a modified form of a retrovirus as a vector The engineered stem cells were then returned to the boy s body Now, he has normal levels of T cells 18

19 HGT Biosafety Considerations Consider the vector (replication competent, incompetent, attenuations) Consider the transgene (oncogene, protooncogene, immune stimulator) Consider mode of delivery (injection, cath lab) Comprehension of risk by populations traditionally not serviced by biosafety professionals Infection Control vs. Biosafety Physicians/Clinicians Pharmacists Nursing Staff Thank You Questions? 19

20 WIRB-Copernicus Group A powerful, responsive and enthusiastic partner 20